The present invention relates to novel compositions of matter and to methods of producing them, and more particularly, to novel hydrogel powders and reticulated hydrogel sponges of diester crosslinked polyglucans of succinic or glutaric acid which are capable of not only absorbing large amounts of fluid, but also have excellent adherence and hemostatic activity when applied to bleeding tissue. The invention also comprises the process of providing hemostasis, employing the compositions of the invention.
A variety of methods has been reported which will produce polyglucan mono- or half-ester succinates and glutarates. For the purposes of this invention, the polyglucan succinates or glutarates may be prepared by any method which results in a completely water-soluble polysaccharide when it has a mono-ester succinate or glutarate degree of substitution above 0.35 in the sodium salt form. (Degree of substitution is the mole ratio of moles of succinate or glutarate per mole of anhydroglucose unit.) We have used both the hot formamide procedure described by Jeanes and Jones [J. Amer. Chem. Society, Vol. 74:6116-7 (1952)] and an adaptation of the aqueous alkaline reaction procedure described in U.S. Pat. No. 2,461,139.
When the polyglucan succinates or glutarates are dried in a prescribed manner, the free acid functions of the mono-ester succinate or glutarate condense with unreacted hydroxyl functions of an adjacent polyglucan molecule, thereby forming diester crosslinks. The product formed is a hydrogel. A product, which has crosslinking to such a degree that the product is water insoluble but swells in water, is termed a hydrogel.
Polyglucan hydrogels have been patented, but heretofore all these hydrogels are diether crosslinked (U.S. Pat. No. 3,208,994 and U.S. Pat. No. 3,042,667). These polyglucan hydrogels cannot be used as bioabsorbable hemostatic agents because they are not biodegradable.
Various types of polyglucans have been marketed for use as bioabsorbable hemostatic agents. The NO.sub.2 -oxidized cellulose (Oxycel) and NO.sub.2 -oxidized regenerated cellulose (Surgicel) products are still used for this purpose. These products have several disadvantages, among which are those found in the package insert of these products:
1. They are very acidic and cause delayed wound healing and in extreme cases even tissue necrosis. PA1 2. They are non-uniform in composition because some residue is left after even 30 days and these residues cause tissue inflammation. PA1 3. They do not adhere tenaciously to bleeding tissue.
Cellulose sulfate and carboxymethylcellulose have also been patented as useful for bioabsorbable hemostatic agents (U.S. Pat. Nos. 2,764,159; 2,772,999; 2,773,000; 2,914,444 and 3,122,479). These products are also only effective as used in their acidic form and, hence, cause delayed healing and severe inflammatory response.
Usher's U.S. Pat. No. 3,765,419 discloses the use of amylose acetates having certain degrees of substitution as hemostatic agents. However, these mono-esters cannot form diester crosslinks and do not provide the desirable hemostatic properties of the products of the present invention.
So far as we are aware, no one has heretofore made a polyglucan bioabsorbable hemostatic agent having a neutral pH that has immediate hemostatic activity and is completely and uniformly absorbed by being enzymatically hydrolyzed to natural metabolites of the host organism.
The reticulated porous hydrogels of the present invention comprise a 3-dimensional network of interconnecting strands of diester-crosslinked polyglucan succinate or glutarate, especially of amylose, said strands being substantially free of "windows" or closed cells. Hence, these compositions can be described as "reticulated sponges". These reticulated sponges have the ability, not only to hold water in their interstices, but also the interconnecting strands themselves swell and retain fluids because the diester-crosslinked polyglucan succinate or glutarate are hydrogels. The overall product is, therefore, called a "reticulated, diester-crosslinked polyglucan hydrogel sponge."
When the aqueous solution of amylose succinate or glutarate is lyophilized in a prescribed manner, in the presence of a reticulating agent, the polyglucan succinate or glutarate solution will melt at a particular point in the freeze-dry cycle so that a reticulated sponge results. This is sometimes referred to in the lyophilization art as "melt-back".
Sponges of starch, amylose, algin, gelatin and collagen have been patented as absorbable hemostatic agents. The process of preparing the starch sponge is described in U.S. Pat. No. 2,597,011. U.S. Pat. No. 3,081,181 describes a process for producing amylose sponges. U.S. Pat. No. 3,653,383 discloses a sponge of algin. The process for preparing the gelatin sponge is described in U.S. Pat. Nos. 2,465,357 and 2,899,262. The process for preparing a collagen sponge is described in Canadian Pat. No. 920,754. Sponges of partially hydrolyzed polyacrylonitrile also have been proposed (U.S. Pat. No. 3,709,842). U.S. Pat. Nos. 2,764,159; 2,914,444 and 3,122,479 describe sponges of ethers of starch, inulin or cellulose. Only the gelatin sponge is being commercially used as an absorbable sponge capable of maintaining hemostasis, being marketed under the name, Gelfoam. These absorbable sponges have one or more deficiencies such as inadequate hemostatic activity, lack of adherence to bleeding tissue, or excessive foreign body response on the part of the user.
So far as we are aware, no one has heretofore made an amylose succinate or amylose glutarate reticulated hydrogel sponge structure itself, nor has anyone made a bioabsorbable sponge which has immediate hemostatic activity, has excellent adherence to the bleeding wound, and is completely and uniformly absorbed by being enzymatically hydrolyzed to natural metabolites of the host organism without causing undue irritation of the tissue or toxic effects.
It is, therefore, an object of the present invention to provide hydrogel powders and reticulated sponges of diester crosslinked polyglucan succinates and glutarates and processes for their preparation.
It is another object of the present invention to provide a process for achieving surgical hemostasis by applying said powders to the bleeding wound surface.
It is also an object of the invention to provide bioabsorbable hydrogel powders and reticulated sponges which do not have the disadvantages of the prior art.
It is an important object of the present invention to provide reticulated hydrogel sponges of diester-crosslinked amylose succinates and amylose glutarates and a process for their preparation.
It is another object of the present invention to provide a process for achieving surgical hemostasis by applying said sponges to the bleeding wound surface.